BEAM-302 Base Editing Sustains Protective AAT, With John Hurst, MBBS, PhD

Initial data from a phase 1/2 trial of BEAM-302, a first-in-human in vivo base-editing therapy for alpha-1 antitrypsin deficiency (AATD), showed a single dose durably raised functional alpha-1 antitrypsin (AAT) above the protective threshold in patients with AATD-associated lung disease, according to John R. Hurst, MD, PhD, professor of respiratory medicine at University College London. Hurst discussed the findings, presented as a poster at the European Respiratory Society (ERS) International Congress, held in Barcelona from September 5-9, in an interview with HCPLive. BEAM-302 uses a guide RNA, adenine base editor, and nickase delivered by lipid nanoparticle to directly correct the disease-causing SERPINA1 mutation in the liver, rather than relying on a viral vector or replacing protein exogenously.

As of the March 14, 2026, data cutoff, 21 patients with AATD-associated lung disease had received single ascending doses of BEAM-302 (15, 30, 60, or 75 mg), with median follow-up ranging from about 7.7 to 17.7 months across dose groups.1 Hurst said a single dose at 60 mg or higher produced sustained total AAT concentrations above the 11-µM threshold associated with protection from emphysema, a threshold established from the natural history of heterozygous carriers of the deficiency allele who do not have significantly elevated lung disease risk.2 The same dose range produced roughly an 80% reduction in circulating mutant Z-AAT.

“For people living with AATD, I don’t think I’ve ever been more optimistic that the future is going to look very different than it does now,” Hurst said.

On safety, Hurst said the profile so far has been consistent with other lipid nanoparticle-delivered therapies: about 40% of patients had grade 1 or 2 infusion-related reactions, generally managed with slower infusion rates or simple interventions like acetaminophen, alongside transient, asymptomatic grade 1 liver enzyme elevations in the first 28 days. No serious treatment-related adverse events had been reported, and Hurst said durability data extending to 18 months for safety and 12 months for efficacy at the 60-mg dose showed no signal of waning response, though longer follow-up is still needed before durability claims can be considered definitive.

Hurst highlighted 2 additional findings from the accompanying poster. First, treated patients showed reduced levels of polymerized Z-AAT protein, a proinflammatory species implicated in AATD-related lung damage, which he said had not previously been demonstrated with any AATD intervention. Second, in a single patient who developed a respiratory infection during follow-up, blood total AAT rose from a steady-state mean of about 14 µM to roughly 23 µM during the infection before settling near 19 µM by month 9, suggesting the corrected gene preserved normal physiologic upregulation of AAT during acute stress rather than producing only a fixed baseline level. Hurst said future trials will need to incorporate clinical and imaging endpoints, including spirometry, gas transfer, CT-based lung density, symptoms, and exacerbation rates, to demonstrate benefit beyond the AAT biomarker itself.

References

1. Hurst JR, van 't Wout EFA, Ashdown T, et al. First-in-human in vivo gene editing for severe alpha-1 antitrypsin deficiency (AATD): initial data from the Phase 1/2 study of BEAM-302. Poster presented at: European Respiratory Society (ERS) International Congress; September 5-9, 2026; Barcelona, Spain.

2. Stolk J. Alpha-1 antitrypsin deficiency: an update. Ann Am Thorac Soc. 2025;22(1):23-31.